Diamino-androstanes and a process for the preparation of the said compounds

ABSTRACT

Curare-type salts of the formula    &lt;IMAGE&gt;  (1a) or   &lt;IMAGE&gt; (1b) wherein Ac is an alkyl carbonyl group containing 1 to 4 carbon atoms in the alkyl moiety and one of R1 and R2, is a methylene group and the other is a group of the formula &gt;N-R2 wherein R2 is an alkyl group containing 1 to 3 carbon atoms, A is halogen and R3 is an alkyl group containing 1 to 4 carbon atoms, or an alkyl group; and a process for the preparation thereof are disclosed.

This is a continuation of application Ser. No. 709,325, filed 28 July1976 now U.S. Pat. No. 4,101,545.

The invention relates to new diamino-androstane derivatives, the acidaddition salts and quaternary salts thereof and to a process for thepreparation of the compounds.

The new diamino-androstane derivatives have the formula ##STR2## wherein

Ac is an alkylcarbonyl group containing 1 to 4 carbon atoms in the alkylmoiety, and one of

R₁ and R₁ ' is a methylene group and the other is a >N--R₂ group,wherein R₂ is a C₁₋₃ alkyl group

n is 1 or 2 and

m is 1, 2, 3 or 4.

The di-quaternary salts of the said diamino-androstanes have the formula##STR3## wherein

Ac, R₁, E₁ ', n and m have the same meanings as defined above.

A is halogen and

R₃ is alkyl having 1 to 3 carbon atoms or an allyl group.

The mono-quaternary salts of the compounds of the formula I have theformula ##STR4## wherein

Ac, n, m, A and R₃ have the same meanings, as defined above.

R₁ ' is methylene and

R₁ is a >N--R₂ group, wherein P₂ has the same meaning as defined above.

The compounds of the formula I of the present invention are asymmetricaldiamines, due to the different meanings of R₁ and R₁ ', i.e. the twoamines attached to the sterane nucleus at the 2β and 16β positions aredifferent, one is a heterocyclic amine compound containing one nitrogenatom and the other amine contains two nitrogen atoms.

In the case of the new di-quaternary salts of the formula Ia regardingthe position of R₃ the two groups deriving from the quaternizing agentare different. One of the R₃ groups is on the heterocyclic amino groupcontaining one nitrogen atom (R₁ or R₁ ' is methylene) and is attachedto this single nitrogen and the other R₃ is on the heterocyclic aminogroup containing two nitrogen atoms (R₁ or R₁ ' is a ═N--R₂ group) andis attached to that nitrogen atom which bears the substituent R₂.

In case of the new mono-quaternary salts of the general formula Ib, R₃is always attached to the heterocyclo containing two nitrogen atoms (R₁or R₁ ' is ═N--R₂), at the nitrogen atom, which bears the substituentR₂.

All the compounds of the formulae I, Ia and Ib are new, and theintermediate products of the synthesis of the formulae II, III and IVare also new. The method for the preparation of the compounds of theformula V used as starting materials is described in Example 1.

The compounds of the formula I are biological active, and the quaternarysalts of the formulae Ia and Ib an outstanding curare type compounds.The intensity of their activity surpasses the activity of the knowncompounds of similar effect.

The compounds of the formulae Ia and Ib show curare type,non-depolarizing neuro-muscular blocking effect, i.e. they inhibit theinplant of the nervous impulse on the striated muscle, do not causehystamine release, do not decrease blood pressure and their effect canbe stopped by neostigmine. The compounds do not show any hormonaleffect.

To determine the intensity and the duration of the activity, catssubjected to anaesthesia and artificial respiration were tested.

The peroneus nerve was irritated electrically and the contraction of thetibialis muscle was registered, by intravenous administration ofdifferent doses of the blocking substances the dose inhibitingcompletely the muscle contraction (ED₁₀₀) was determined. The timebetween the starging effect and the restoration of the normal musclereaction was measured. The data of the following table are related tothe dose causing complete inhibition. As a referential substancepancuronium bromide (Negwer (1971) 4821) was used. (Advances in SteroidBiochemistry and Pharmacology (Briggs), W. R. Buckett: Aspects of thePharmacology of Aminosteroids. 56-59, Br. J. Pharmac. Chemother 32.671-682 (1968). Arzneimittel-Forsch. 19, 1723-1726 (1969).

    ______________________________________                                                                     Duration of                                      Compound        ED.sub.100 /mcg/kg                                                                         effect/minutes                                   ______________________________________                                        2β-(4-Dimethyl-piperazino)-                                              16β-N-methyl-piperidino-                                                 3α,17β-diacetoxy-5α-                                         androstane-dibromide                                                                          4.5          16                                               2β-N-Methyl-p-peridin-16β-                                          (4-dimethyl-piperazino)-                                                      3α,17β-diacetoxy-5α-                                         androstane-dibromide                                                                          7.2          18                                               Pancuronium bromide                                                                           18.0         23                                               ______________________________________                                    

The table shows, that the effective doses of the new compounds are 2.5to 4 times smaller than that of pancuronium bromide and the duration ofthe effect is about 30 to 40% shorter.

The new compounds of the invention can be used in the first place forfacilitating the intubation, alleviating the muscle spasms in the shocktherapy or for hypomyotomia in any spasmodic diseases of the striatedmuscles.

The present invention is further directed to a process for thepreparation of the compounds of the formula I-- wherein Ac, R₁ and R₁ ',n and m are as defined above, and of the diquaternary salts thereof ofthe formula Ia-- wherein Ac, R₁, R₁ ', n and m, A and R₃ are as definedabove or of the mono-quaternary salts thereof of the formula Ib, whereinthe substituents are as defined above, which comprises reacting acompound of the formula ##STR5## wherein X is halogen, with a compoundof the formula ##STR6## wherein n and m are as defined above and R₁ ' ismethylene or >N-R₂ --

wherein R₂ is given above and adding, if desired a hydrogen halogenideto the reaction mixture and reducing the obtained compound of theformula ##STR7## wherein n and m are as defined above, R₁ ' in methyleneor >N-R₂ --

wherein R₂ is a C₁₋₃ alkyl, Y₁ is halogen, Y₂ is hydroxyl or Y₁ and Y₂form together epoxy, and reacting the compound of the formula ##STR8##thus formed-- wherein R₁ ', n, m, Y₁ and Y₂ are given above with acompound of the formula ##STR9## wherein R₁, n and m have the samemeanings as given above and acylating the obtained compound of thegeneral formula ##STR10## wherein R₁, R₁ ', n and m have the samemeanings as given above-- with an aliphatic acarboxylic acid containing1 to 5 carbon atoms or a reactive derivative thereof, and converting, ifdesired, the compound of the formula I thus obtained into an acidaddition salt or into a quaternary salt thereof of the formula Ia or Ib.

The new compounds of the invention are prepared from17-halo-androsta-2,16-diene of the formula V, preferably from the17-iodo or 17-bromo derivative and from a heterocyclic amine of theformula VI.

The compounds of the formula VI are five to eight membered heterocyclicamines containing 2 nitrogens and the most advantageous representativesthereof are for example N-alkyl-piperazine, N-alkyl-pyrimidine,N,alkyl-imidazolidine, piperidine, pyrrolidine, heptamethylene imineetc. The alkyl chain of the N-alkyl derivatives contain 1 to 3 carbonatoms.

The compound of the formula V or VI is reacted alone or in the presenceof an organic solvent, preferably acetonitrile or benzene, at atemperature in the range of from 10° C. to the boiling point of thereaction mixture. The reaction is accomplished within 20 to 70 hours atroom temperature and within 10 to 120 minutes at the boiling point ofthe reaction mixture.

The compound of the formula IV obtained after the reaction is complete--wherein Y₁ and Y₂ stand together for epoxy-- is isolated by evaporationor by extraction and is purified, if desired, by crystallization.

According to another preferable embodiment of the process of theinvention the reaction mixture obtained after the reaction of thecompounds of the formulae V and VI, is evaporated and the residue isdissolved in an inert organic solvent, preferably in an ether orchlorinated hydrocarbon and a hydrogen halogenide is added to theobtained solution. The hydrogen halogenide salt of the compound of theformula IV containing halogen as Y₁ and hydroxyl as Y₂ is separated fromthe reaction mixture. This method is mainly applied when the compoundsof the formula IV can not be isolated in the form of a base by a simplemethod. The compound of the formula IV obtained by any of the previousmethods, is reduced. As a reducing agent alkali metal borohydrides oralkoxy metal hydrides e.g. sodium borohydride,sodium-bis-(2-methoxy-ethoxy)-lithium-aluminiumhydride or -borohydrideor -trimethoxyborohydride may be used. The reduction is conducted in anorganic solvent, preferably in a lower aliphatic alcohol or chlorinatedhydrocarbon or preferably in a mixture of both. The reduction is carriedout at a temperature of below 30° C. When using the starting material ofthe formula IV in the form of a halogen acid-addition salt, an acidbinding agent e.g. an alkali metal hydroxide or an alkali metalcarbonate is also added.

As a reaction product a compound of the formula III is formed, which isisolated for example by evaporation or filtration, and is purified, ifdesired, by crystallization or by stirring and/or heating the mixturewith a solvent dissolves the impurities but not the product.

The formed compound of the formula III is repeatedly reacted with anamine of the formula VI. The amine of the formula VI used for the secondtime contains a different substituent R₁. The amine of the formula VI isused in a large excess related to the compound of the formula III i.e.in a molar ratio of 1:40 to 1:50. The reaction is conducted in a bombtube, preferably in the presence of water at an environmentaltemperature of 70° to 160°C., 130-150° C. at a pressure of a fewatmospheres, preferably at the tension of the mixture itselfcorresponding to the temperature. The compound of the formula II thusobtained is isolated from the reaction mixture by evaporation or bypouring the compound of the formula II, preferably into water when usinga starting material of the formula VI of higher boiling point, and bysalting it out.

The compound of the formula II prepared according to the methoddescribed above is converted to the compound of the formula I byacylation.

The acylation may be conducted in an inert organic solvent, preferablyin the presence of a tertiary amine, for example in pyridine. Asacylating agents aliphatic carboxylic acids having 1 to 5 carbon atomsor preferably reactive derivatives of aliphatic carboxylic acids of 1 to5 carbon atoms e.g. the corresponding acid halogenides or acidsanhydrides and be used.

According to a preferable embodiment of the process the acylating agentis used as a solvent, preferably an aliphatic carboxylic acid of 1 to 5carbon atoms and/or the corresponding acid anhydride, preferably aceticacid anhydride or propionic acid anhydride or a Lewis acid in acatalytical amount such as iron(III)chloride, antimony chloride, tinchloride or, preferably zinc chloride is added to the solution. Theformed compound of the formula I may be isolated from the reactionmixture by alkalizing the mixture to pH=10 followed by purification.Pharmaceutically acceptable, non-toxic organic or inorganic acidaddition salts can be formed, if desired, from the compounds of theformula I. Among the inorganic acid-addition salts, preferably halogenacid-addition salts, and among the organic acid addition salts acetatesand gluconates are preferred.

Di-quaternary and mono-quaternary salts of the formulae Ia and Ib may beformed if desired, from the compound of the formula I. In order toobtain the quaternary salts the compounds of the formula I may bereacted with alkyl halides of 1 to 5 carbon atoms e.g. methyl, ethyl,propyl, i-butyl halides, preferably with the correspondingbromo-compound or allyl halides, preferably allyl bromide.

The quaternary salts are formed in an inert organic solvent e.g. inchlorinated hydrocarbons, preferably methylene chloride, in acetone,nitromethane, acetonitrile, etc.

The reaction is conducted at atmospheric pressure at a temperature inthe range of from room temperature to the boiling point of the mixtureor in a bomb tube under pressure, preferably at the tension of themixture itself corresponding to the temperature.

The obtained product is isolated by filtration or by evaporation of themixture or by adding acetone or diethylether to the reaction mixture andisolating the precipitated salt.

When preparing mono-quaternary salts of the formula Ib the quaternizingagent is used in a small excess and the starting material is dissolvedin a small amount of solvent and thus the formed mono-quaternary salt isprecipitated from the reaction mixture in the instant of itsformulation.

When preparing diquaternary salts of the formula Ia in the quaternizingagent is used in a 10 to 20-fold molar access.

The details of this invention are illustrated by the following Examples:

EXAMPLE 1 2α,3α-epoxy- 17-oxo-16β-N-methyl-piperazino-5α-androstane.

25 g. (0.068 mole) of 2α,3α,16α,17α-diepoxy-17β-bromo-5α-androstane aredissolved in 170 ml. of acetonitrile, whereafter 20.5 ml. (0.190 mole)of N-methyl-piperazine are added. The reaction mixture is allowed tostand for 24 hours and heated under reflux for 15 minutes. The reactionmixture is evaporated to dryness at reduced pressure and the residue isdissolved in methylene chloride. The methylene chloride solution iswashed with water until the pH achieves the value of 7, followed by theseparation of the 2 layers. The organic layer is dried over sodiumsulfate, filtered and the filtrate is evaporated at reduced pressue. Theresidue is purified by stirring with ether, the crystallized product isfiltered and dried.

Yield: 20.1 g. (76.5%) of2α,3α-epoxy-17-oxo-16β-N-methyl-piperazino-5α-androstane. M.p.: 132-134°C.

[α]_(D) ²⁵ =+121.2° (c=1, in chloroform).

Analysis for the formula C₂₄ H₃₈ N₂ O₂ : Calculated: C, 74.60%; H,9.85%; N, 7.24%. Found: C, 74.39%; H, 9.97%; N, 7.12%.

2α,3α,16α,17α-epoxy-17β-bromo-5α-androstane used as the startingmaterial is prepared as follows:

200 g. (0.735 mole) of 17-oxo-5α-androst-2-ene are dissolved in 2000 ml.of ethanol, whereafter 360 ml. of triethylamine and 880 ml. of 98%hydrazine hydrate (14.7 mole) are added. The reaction mixture is heatedunder reflux for 2 hours and cooled to room temperature. The reactionmixture is then added under vigorous stirring to 20 l. of icy water. Theprecipitated product is filtered, washed with water to removetriethylamine and dried over phosphorus pentoxide in vacuo at roomtemperature. The crude product is recrystallized from n-hexane.

Yield: 185 g. (91%) of 17-hydrazone-5α-androst-2-one.

M.p.: 124° to 132° C.

[α]_(D) ²⁵ =+98° (c=1, in chloroform).

Analysis for the formula O₁₉ H₃₀ N₂ : Calculated: C, 79.60%; H, 10.50%;N, 9.70%. Found: C, 79.42%; H, 10.60%; N, 9.61%.

30 g. (0.100 mole) of 17-hydrazone-5α-androst-2-ene are dissolved in 200ml. of anhydrous pyridine and the solution is cooled to -10° C. Asolution of 30 g. (0.168 mole) of N-bromo-succinic imide in 330 ml. ofpyridine are added at 0-(-10) ° C. The reaction mixture is stirred untilnitrogen evolution ceases and added to 3 l. of 5% icy hydrochloric acidsolution. The precipitated substance is extracted with 300 to 400 ml. ofcarbon tetrachloride and the carbon tetrachloride layers are obtained.The combined tetrachloride solution is washed with 5% aqueoushydrochloride acid solution and with water until pH=7. The neutralcarbon tetrachloride solution is dried over sodium sulfate, filtered,and the filtrate is evaporated to dryness. The oily residue is trituatedwith 100 ml. of n-hexane and the precipitated by-product is filtered.The filtrate is evaporated and the residue is triturated with 50 ml. ofa 9:1 mixture of ethanol and acetone. The precipitated product isfiltered and dried.

Yield: 23.4 g. (66%) of 17-bromo-5α-androsta-2,16-diene.

M.p.: 76-77° C.

[α]_(D) ²⁵ =71.2° (c=1, in chloroform).

Analysis for the formula C₁₉ H₂₇ Br: Calculated: C, 71.35%; H, 8.07%;Br, 23.80%. Found: C, 71.21%; H, 8.15%; Br, 23.57%.

17-hydrazone-5α-androst-2-ene and N-iodo-succinic imide are reacted asdescribed above to give the corresponding iodo compound.

Yield: 66% of 17-iodo-5α-androsta-2,16-diene.

M.p.: 71-72° C.

[α]_(D) ²⁵ =56.1° (c=1. in chloroform).

Analysis for the formula C₁₉ H₂₇ J:

Calculated: C, 59.70%; H, 7.07%; J, 33.13%.

Found: C, 59.52%; H, 6.90%; J, 32.9%.

90g. (0.27 mole) of 17-bromo-5α-androsta-2,16-diene are dissolved in1100 ml. of chloroform and a 7.2% solution (0.81 mole) ofm-chloro-perbenzoic acid in 1600 ml. of chloroform are added to roomtemperature. The reaction mixture is allowed to stand at roomtemperature for 24 hours whereafter the mixture is cooled to 0° C. andunder cooling with ice a 10% aqueous sodium hydroxide solution and waterare added to remove the acid and to achieve a pH=7. After separation thechloroform layer is dried over sodium sulfate, filtered and the filtrateis evaporated to dryness. The oily residue is triturated with 100 ml. ofether, filtered and the crude product on the filter is recrystallizedfrom acetonitrile.

Yield: 85.7 g. (87%) of 2α,3α,16α,17α-diepoxy-17β-bromo-5α-androstane.

M.p.: 160-162° C.

[α]_(D) ²⁵ =+73.5° (c=1, in chloroform).

Analysis for the formula C₁₉ H₂₇ BrO₂ Calculated: C, 62.00%; H, 7.35%;Br, 21.80%.

Found: C, 61.79%; H, 7.20%; Br, 21.7%.

2α,3α,16α,17α-diepoxy-17β-iodo-5α-androstane can be prepared by themethod described above with a yield of 81% from17iodo-5α-androsta-2,16-diene.

EXAMPLE 22β-chloro-3α(-hydroxy-17-oxo-16β-piperidino-5α-androstane-hydrochloride

12.5 g (0.034 mole) of 2α,3α,16α,17α-diepoxy-17-bromo-5α-androstane aredissolved in 85 ml. of acetonitrile, whereafter 10 ml. (0.1 mole) ofpiperidine are added. The reaction mixture is heated under reflux for 1hour, and the reaction mixture is evaporated at reduced pressure. Theresidue is dissolved in diethylether and the ether solution is washedwith water until pH=7. The two layers are separated. The product isprecipitated from the organic layer with 6% ethereal hydrochloric acidsolution in the form of a chlorohydrate salt. The precipitated acidaddition salt is filtered, washed with ether and dried in vacuo at 60°.

Yield: 10.3 g. (70%) of 2β-chloro-3α-hydroxy-17-oxo-16β-piperidino-5α-androstane-hydrochloride.

M.p.: 237-239° C. (decomposition).

Analysis for the formula C₂₄ H₃₉ O₂ NCl₂ :

Calculated: C, 64.8% ; H, 8.7 %; Cl, 16.0 %.

Found: C, 64.6 %; H, 9.0 %; Cl, 15.7 %.

EXAMPLE 3 2α,3α-epoxy-17β-hydroxy-16β-N-methyl-piperazino- 5α

15 g. (0.038 mole) of 2α,3α-epoxy-17-oxo-16β-N-Methyl-piperazino-5α-androstane are dissolved in the mixture of 45 ml.of methylene chloride and 120 ml. of methanol, whereafter 12 g. (0.31mole) of sodium borohydride are added at a temperature of below 30° C.When the addition is complete, the product of the reduction iscrystallized. The crystalline solution is stirred vigorously for 12hours, whereafter the solvent is distilled at reduced pressure at atemperature of below 40° C. The residue is triturated with water, thecrystallized product is filtered, dissolved in chloroform and washedwith 5% aqueous sodium hydroxide solution and with water until pH= 7.The layers are separated. The chloroform layer is dried on sodiumsulfate, filtered and the filtrate is evaporated to dryness. The residueis recrystallized from acetonitrile.

Yield: 11.7 g. (77.2%) of 2α,3α-epoxy-17β-hydroxy-16β-N-methyl-piperazino-5.alpha.-androstane.

M.p.: 149-153° C.

[α]_(D) ²⁵ =+27.1° (c = 1. in chloroform).

Analysis for the formula C₂₄ H₄₀ N₂ O₂ ;

Calculated: C, 74.20 %; H, 10.30 %; N, 7.22 %.

Found: C, 74.01 %; H10.41 %; N, 7.07 %.

Example 4 2β-chloro-3α, 17β-dihydroxy-16β-piperidino-5α-androstane.

25 g. (0.056 mole) of2β-chloro-3α-hydroxy-17-oxo-16β-piperidino-5α-androstane-hydrochlorideare dissolved in the mixture of 52 ml. of methylene chloride and 125 ml.of methanol. Under vigorous stirring 2.75 g. (0.069 mole) of pulverizedaudium hydroxide and at a temperature of 15-20° C. 12.5 g. (0.33 mole)of sodium borohydride are added to the solution. The productprecipitated immediately. The crystalline solution is stirred for 5hours, whereafter the product is filtered and washed with water. Themother liquor is evaporated at reduced pressure at a temperature ofbelow 30° C., the residue is triturated with water, the mixture isfiltered and the second crop above the filter is washed with water. The2 fractions are combined. dried in vacuo at 50° C., followed byrecrystallization from acetone.

Yield: 20.2 g. (88 %) of2β-chloro-3α,17β-dihydroxy-16β-piperidino-5α-androstane.

M.p.: 232-234° C.

Analysis: for the formula C₂₄ H₄₀ ClO₂ N:

Calculated: C, 70.3%; H, 9.7 %; Cl, 8.6 %.

Found: C, 70.0 %; H, 9.9 %; Cl, 8.8 %.

EXAMPLE 52β-piperidino-16β-N-methyl-piperazino-3α,17β-dihydroxy-5α-androstane

14.8 g. (0.03 mole) of2α,3α-epoxy-17β-hydroxy-16β-N-methyl-piperazine-5.alpha.-androstane aredissolved in 168 ml. (1.65 mole) of piperidine and 24 ml. of water,whereafter the reaction mixture is heated in a bomb tube for 72 hours atan environmental temperature of 140° C. After the reaction isaccomplished the reaction mixture is evaporated at reduced pressure. Theresidue is stirred in acetonitrile, filtered and the product above thefilter is heated under reflux in acetonitrile. The crystallized productis filtered and dried.

Yield: 12.4 g. (69.0 %) of2β-piperidino-16β-N-methyl-piperazino-3α,17β-dihydroxy-5α-androstane.

M.p.: 154-156° C.

[α]_(D) ²⁵ =+84.5° (c = 1, in chloroform).

Analysis for the formula C₂₉ H₅₁ N₃ O₂.H₂ O: Calculated: C, 71.0 %; H,10.80 %; N, 9.26 %.

Found: C, 70.8 %; H, 10.97 %; N, 9.10 %.

EXAMPLE 62β-N-methyl-piperazino-16β-piperidino-3α,17β-dihydroxy-5α-androstane.

The compound was prepared according to Example 5 from2β-chloro-3α-,17β-dihydroxy-16β-piperidino-5α-androstane and fromN-methyl-piperazine.

Yield: 67.0% of2β-N-methyl-piperazino-16β-piperidino-3α,17β-dihydroxy-5α-androstane.

M.p.; 230-234° C.

[α]_(D) ²⁵ =+81.7° (c =1, in chloroform).

Analysis for the formula C₂₉ H₅₁ N₃ O₂.H₂ O:

Calculated: C, 71.0 %; H, 10.80 %; N, 9.26 %.

Found: C, 70.8 %; H, 10.70 %; N, 9.05 %.

Example 72β-piperidino-16β-N-methyl-piperazino-3α,17β-diacetoxy-5α-androstane.

3g (0.0063 mole) of2β-piperidino-16β-N-methyl-piperazino-3α,17β-dihydroxy-5α-androstane aredissolved in the mixture of 13 ml. of acetic acid andydride and 1 ml. ofglacial acetic acid, whereafter 0.3 g. of zinc chloride is given to thesolution. The reaction mixture is stirred for 12 hours, whereafter theexcess acetic acid andydride is decomposed by adding 40 ml. of water.The solution is cooled to 0° to 5° C. and 15 % aqueous sodium hydroxidesolution is added at the same temperature until the pH reaches the valueof 9-10. The precipitated fluffy substance is immediately extracted withether. The ether extract is washed with an aqueous solution saturatedwith sodium chloride until neutral state. The layers are separated, theether layer is dried over sodium sulfate and filtered. The filtrate istreated with 3 g. of decolourising silicagel, the mixture is filteredand evaporated to dryness. The product is crystallized from the residueby trituration with hexane, filtered and dried.

Yield: 2.6 g. (73.5%) of2β-piperidino-16β-N-methyl-piperazino-3α,17β-diacetoxy-5α-androstane.

M.p.: 95-98° C.

[α]_(D) ²⁵ =+33.9° (c=1, in chloroform).

Analysis for the formula C₃₃ H₅₅ N₃ O₄ :

Calculated: C, 71.20%; H, 3.00%; N, 7.54%.

Found: C, 71.01%; H, 8.87%; N, 7.36%.

EXAMPLE 82β-N-methyl-piperazino-16β-piperidino-3α-17β-diacetoxy-5α-androstane

The compound is prepared by acylation of2β-N-methyl-piperazino-16β-piperidino-3α,17α-dihydroxy-5α-androstaneaccording to the method described in Example 7.

Yield: 72.0%.

[α]_(D) ²⁵ +29.4° (c=1, in chloroform).

Analysis for the formula C₃₃ H₅₅ N₃ O_(4:)

Calculated: C, 71.20%; H, 9.00%; N, 7.54%.

Found: C, 70.9%; H, 8.8%; N, 7.3%.

EXAMPLE 92β-N-methyl-piperidino-16β-(4-dimethyl-piperazino)-3β,17.alpha.-diacetoxy-5α-androstane-dibromide

1 g. (0.0018 mole) of2β-piperidino-16β-N-methyl-piperazino-3α,17β-diacetoxy-5α-androstane isdissolved in 20 ml. of acetone whereafter 10 ml. of 5% solution ofmethyl bromide in acetone is added. The reaction mixture is allowed tostand for 48 hours at room temperature. The precipitated quaternary saltis filtered, triturated with acetone and ether and filtered. Thefiltered precipitation is heated under reflux in acetone, thecrystalline solution is cooled to room temperature, filtered and dried.

Yield: 1.2 g. (87.2%) of2β-N-methyl-piperidino-16β-(4-dimethyl-piperazino)-3α,17.beta.-diacetoxy-5α-androstane-dibromide.

M.p.: 260-264° C. (decomposition).

Analysis for the formula: C₃₅ H₆₁ N₃ BrO₄.H₂ O:

Calculated: C, 55.00%; H, 8.24%; Br, 20.90%; N, 5.50%.

Found: C, 54.81%; H, 8.10%; Br, 20.51%; N, 5.40%.

EXAMPLE 102β-(4-dimethyl-piperazino)-16β-N-methyl-piperidino-3α,17.beta.-diacetoxy-5α-androstane-dibromide

1.3 g. (2.34 mmole) of 2α-N-methyl-piperazino-16β-piperidino-3α,17β-diacetoxy-5α-androstane are dissolved in themixture of 10 ml. of acetone and 20 ml. of acetonitrile. 32 ml. of asolution of 8.4% methyl bromide (20 mmole) in acetone are added. Thereaction mixture is allowed to stand for 98 hours at room temperatureand the precipitated quaternary salt is isolated by the method describedin Example 9.

Yield: 1.4 g. (78.5%) of2β-(4-dimethyl-piperazino)-16β-N-methyl-piperidino-3α,17.beta.-diacetoxy-5α-androstane-dibromide.

M.p.: 248-252° C. (decomposition).

[α]_(D) ²⁵ =-14.3° (c=1, in chloroform).

Analysis for the formula C₃₅ H₆₁ Br₂ N₃ O₄.H₂ O:

Calculated: C, 55.00%; H, 8.24%; N, 5.5%; Br, 20.9%.

Found: C, 54.75%; H, 7.96%; N, 5.42%; Br, 20.6%.

EXAMPLE 112β-(4-dimethyl-piperazino)-16β-piperidino-3α,17β-diacetoxy-5α-androstane-bromide

2 g. (3.6 mmole) of2β-N-methyl-piperazino-16β-piperidino-3α,17β-diacetoxy-5α-androstane aredissolved in 20 ml. of acetone whereafter 12 ml. (10.6 mmole) of 8.4%methyl bromide in acetone are added. The reaction mixture is allowed tostand at room temperature, whereafter the precipitated quaternary saltis filtered, washed with acetone and ether and the precipitate ispurified by mixing it with acetone, the mixture is filtered and dried.

Yield: 1.5 g. (62.5%) of2β-(4-dimethyl-piperazino)-16β-piperidino-3α,17β-diacetoxy-5α-androstane-bromide.

M.p.: 234-237° C. (decomposition).

[α]_(D) ²⁵ =+12.8° (c=1, in chloroform).

Analysis for the formula C₃₄ H₅₈ BrN₃ O₄.H₂ O:

Calculated: C, 61.4%; H, 8.7%; N, 6.1%; Br, 11.7%.

Found: C, 61.1%; H, 8.9%; N, 5.9%; Br, 11.3%.

What we claim is:
 1. A process for the preparation of a di-quaternarysalt of the formula ##STR11## wherein Ac is an alkyl carbonyl grouphaving 1 to 4 carbon atoms in the alkyl moiety, one ofR₁ and R₁ ' is amethylene group and the other is a group of the formula >N--R₂ whereinR₂ is a C₁₋₃ alkyl group, R₃ is an alkyl group containing 1 to 4 carbonatoms or an allyl group, A is halogen, or of a mono-quaternary salt ofthe formula ##STR12## wherein Ac, A and R₃ have the same meaning asdefined above, R₁ ' is a methylene group and R₁ is a group of theformula >R--R₂ wherein R₂ is as defined above, which comprisesselectively reacting the 16,17 epoxy group of a compound of the formula##STR13## wherein X is halogen--with a compound of the formula ##STR14##in the presence of a hydrogen halide wherein R₁ ' is a methylene groupor a >N--R₂ group to form a compound of the formula ##STR15## wherein Y₁^(a) is halogen and Y₂ ^(a) is hydroxy; or selectively reacting the16,17-epoxy group of a compound of the formula ##STR16## wherein X ishalogen with a compound of the formula ##STR17## wherein R₁ ' is amethylene group or a N--R₂ group, to form a compound of the formula##STR18## wherein Y₁ ^(b) and Y₂ ^(b) form together an epoxy group, andreducing the compound IVa or IVb to form a compound of the formula:##STR19## wherein Y₁ is halogen, Y₂ is hydroxyl or Y₁ and Y₂ formtogether an epoxy group;reacting the compound formed above with acompound of the formula: ##STR20## to yield a compound of the formula##STR21## acylating the compound formed above with a C₁ to C₅ aliphaticcarboxylic acid, C₁ to C₅ aliphatic carboxylic acid anhydride or C₁ toC₅ aliphatic carboxylic acid halogenide to yield a compound of theformula ##STR22## and converting the compound above into a quaternarysalt thereof of the formula 1a or 1b.
 2. A process as claimed in claim1, which comprises reducing the compounds of the formulae IVa or IVbwith a metal hydride.
 3. A process as claimed in claim 1, whichcomprises conducting the reduction at a temperature of below 30° C.
 4. Aprocess as claimed in claim 1, which comprises reacting the compounds ofthe formulae III and IVa or IVb at a temperature of 70° to 160° C.
 5. Aprocess as claimed in claim 1, which comprises acylating the compound ofthe formula II with a C₁₋₅ acid anhydride.
 6. A process as claimed inclaim 1, which comprises acylating in the presence of a Lewis acid.
 7. Aprocess as claimed in claim 1, which comprises conducting the reactionsin a solvent.
 8. A process as claimed in claim 1, which comprisespreparing2β-N-methyl-piperidino-16β-(4-dimethyl-piperazine)-3α,17.beta.-diacetoxy-5α-androstane-dibromide.9. A process as claimed in claim 1, which comprises preparing2β-(4-dimethyl-piperazino)-16β-N-methyl-piperidino-3α,17.beta.-diacetoxy-5α-androstane-dibromide.10. A process as claimed in claim 1, which comprises preparing2β-(4-dimethyl-piperazino)-16β-piperidino-3α-17β-diacetoxy-5α-androstane-bromide.